The intestinal fatty acid binding protein (IFABP) is present in humans in two forms which differ by a alanine to threonine substitution at amino acid 54. In vitro, the threonine form (Thr54) is characterized by a two-fold higher binding affinity for long chain fatty acids than the alamino form (Ala54). The Thr54 form also is associated with higher plasma insulin concentrations and insulin resistance in the Pima Indians. This project examines whether the in vitro binding differences are physiologically significant. Triglyceride and fatty acid responses and of lipid oxidation were determined following a standard test meal in healthy subjects homozygous for either the Thr54 form or the Ala54 form of IAFBP. A total of 18 subjects (9 Thr54 and 9 Ala54 homozygotes, 10 males and 8 females) have been studied, thus far. The groups were similar in age, weight, and % body fat. In response to a mixed meal, plasma NEFA concentrations tended to be higher in individuals homozygous for the Thr54 allele than in sex-matched, comparably obese Ala54 controls. On average, NEFA concentrations were ~15% higher in Thr54 homozygotes than in controls, comparable to the previously reported difference. This difference approached statistical significance (P = 0.07) and would likely have been significant had the sample size been larger. The largest differences between groups occurred later in the course of the study, after subjects had been fasting for several hours, rather than immediately after the meal. NEFA concentrations peaked earlier (~7 h) and ~20% higher in Thr54 homozygotes following the high fat feeding. The polymorphism in IFABP did not appear to affect either skeletal muscle or adipose tissue membrane phospholipid fatty acid composition. Plasma insulin concentrations were higher in subjects homozygous for the Thr54 allele. The difference was most marked following a high fat feeding. The higher insulin responses may be due, in part, to the insulin resistance we have previously documented in individuals with the Thr54 allele. Thus, as might be expected from the tissue distribution of the protein, the Thr54 polymorphism in the IFABP appears to affect primarily post-prandial responses to dietary fat. This effect is subtle, however. This protocol has been terminated.